l-651896 and Dermatitis

The synthesis, biological evaluation, and structure-activity relationships of a series of 1-naphthols bearing carbon substituents at the 2-position are described. These compounds are potent inhibitors of the 5-lipoxygenase from RBL-1 cells and also inhibit bovine seminal vesicle cyclooxygenase. Structure-activity relationships for these two enzymes are different, implying specific enzyme inhibition rather than a nonspecific antioxidant effect. 2-(Aryl-methyl)-1-naphthols are among the most potent 5-lipoxygenase inhibitors reported (IC50 values generally 0.01-0.2 microM) and show excellent antiinflammatory potency in the mouse arachidonic acid ear edema model. To study the effects of structure on in vitro and in vivo activity, four general features of the molecules were varied: the 2-substituent, the 1-hydroxyl group, substitution on the naphthalene rings, and the 1,2-disubstituted naphthalene unit itself. 2-Benzyl-1-naphthol (5a, DuP 654) shows a very attractive profile of topical antiinflammatory activity and is currently in clinical trials as a topically applied antipsoriatic agent.

Topics: Animals; Arachidonate Lipoxygenases; Arachidonic Acid; Arachidonic Acids; Chemical Phenomena; Chemistry; Dermatitis; Ear Diseases; Edema; Leukemia, Basophilic, Acute; Lipoxygenase Inhibitors; Molecular Structure; Naphthols; Rats; Structure-Activity Relationship; Tumor Cells, Cultured

The biochemical and biological profile of a topical anti-inflammatory agent, 2,3-dihydro-6-[3-(2-hydroxymethyl)phenyl-2-propenyl]-5-benzofuranol (L-651,896 inhibited the 5-lipoxygenase of rat basophilic leukemia cells with an IC50 of 0.1 microM and leukotriene synthesis by human PMN and mouse macrophages with IC50 values of 0.4 and 0.1 microM respectively. L-651,896 also inhibited prostaglandin E2 synthesis by mouse peritoneal macrophages (IC50 = 1.1 microM). This compound inhibited ram seminal vesicle cyclooxygenase activity at considerably higher concentrations, and this effect was directly related to substrate concentration. When applied topically to the mouse ear, L-651,896 lowered elevated levels of leukotrienes associated with arachidonic acid-induced skin inflammation and delayed hypersensitivity induced by oxazolone. However, while L-651,896 inhibited the increased vascular permeability induced by arachidonic acid, it had no effect on the edema associated with the immune-based response to oxazolone in the same tissue. Thus, it is possible that leukotrienes may play a role in some but not all inflammatory responses.

Topics: Administration, Topical; Animals; Anti-Inflammatory Agents; Arachidonate Lipoxygenases; Benzofurans; Dermatitis; Dinoprostone; Humans; Hypersensitivity, Delayed; Leukemia, Experimental; Lipoxygenase Inhibitors; Macrophages; Neutrophils; Oxazolone; Prostaglandin-Endoperoxide Synthases; Prostaglandins E; SRS-A